Discovery of aminoheterocycles as a novel β-secretase inhibitor class: pH dependence on binding activity part 1

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 11; pp. 2977 - 2980
• Main Authors: Stachel, Shawn J., Coburn, Craig A., Rush, Diane, Jones, Kristen L.G., Zhu, Hong, Rajapakse, Hemaka, Graham, Samuel L., Simon, Adam, Katharine Holloway, M., Allison, Tim J., Munshi, Sanjeev K., Espeseth, Amy S., Zuck, Paul, Colussi, Dennis, Wolfe, Abigail, Pietrak, Beth L., Lai, Ming-Tain, Vacca, Joseph P.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-06-2009; Elsevier
• Subjects: Alzheimer’s disease; Aminoheterocycles; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; b-Secretase; BACE-1; Biological and medical sciences; Crystallography, X-Ray; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Hydrogen-Ion Concentration; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Protein Binding; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Structure-Activity Relationship; b-Secretase; Aminoheterocycles; Alzheimer’s disease; BACE-1; Nitro compound; Five membered ring; Nitrogen heterocycle; Modeling; Structure activity relation; Chlorine Organic compounds; Molecular model; pH; β-secretase; Aspartic endopeptidases; Alzheimer's disease; Ether; Enzyme; Benzene derivatives; Enzyme inhibitor; Inhibitor enzyme complex; Antialzheimer agent; In vitro; Amyloid precursor protein; Peptidases; Medium effect; Hydrolases
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.04.033

A novel series of heteroaromatic BACE-1 inhibitors is described. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, a pH dependent effect on the binding affinity as a result of the intrinsic pKa of these inhibitors and the pH of the BACE-1 enzyme binding assay is discussed.
We have developed a novel series of heteroaromatic BACE-1 inhibitors. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, we have discovered a pH dependent effect on the binding affinity as a result of the intrinsic pKa of these inhibitors and the pH of the BACE-1 enzyme binding assay.